Impaired awareness of hypoglycemia (IAH), which is a diminished ability to perceive the onset of hypoglycemia (HG) and typically co-exists with a reduction in the counterregulatory hormone responses (CRR) to HG, triples the risk of experiencing potentially fatal severe hypoglycemia for patients with type 1 diabetes (T1D). Our long- term goal remains to identify how recurrent HG leads to the clinical syndrome of IAH in T1D. Here we will study the cerebral mechanisms of IAH in the setting of T1D following exposure to experimental recurrent HG and test the hypothesis that recurrent HG in T1D leads to an upregulation in brain glucose transport and alterations in glutamatergic and GABAergic tone. We will use MRS methodology that permits evaluation of cerebral cortex and hypothalamus in the same session to simultaneously evaluate the cerebral correlates/mediators of impaired awareness and impaired CRR. High MR data quality and reproducibility will be ensured by using high field MR scanners and technical advances we made during the last grant cycle (automated voxel placement, real-time voxel tracking, dynamic frequency and shim updates). Continuous glucose monitoring and actigraphy will be used to chronicle glucose variability and activity/exercise/sleep during the weeks before each experiment to assess the impact of these variables on IAH. Our specific aims are: Aim 1: To measure the neurochemical response to hypoglycemia in T1D (N=50) before and after induction of IAH. Neurochemical profiles including glutamate, GABA and glucose will be measured in the frontal cortex, a region associated with IAH in prior neuroimaging work, and in hypothalamus, which regulates CRR, during euglycemia and HG at 7 tesla, at baseline and after a recurrent HG protocol that robustly induces IAH in patients with T1D and NAH. Aim 2: To measure cerebral glucose transport in T1D (N=50) before and after induction of IAH. Kinetic parameters for glucose transport will be measured in the frontal cortex and hypothalamus using hyperglycemic clamps at 3 tesla at baseline and after recurrent HG. These experiments will establish if recurrent HG alters cerebral glucose availability and glutamate and GABA tone in T1D and if these cerebral adaptations are associated with the development of blunted CRR and diminished symptoms in patients with T1D. In addition, we will learn how glycemic excursions and activity/sleep impact the induction of IAH. These observations are expected to lead to new ways to prevent and treat this life-threatening condition in T1D.